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BackgroundThe extents of generic-reference and generic-generic average bioequivalence and intra-subject variation of on-market drug products have not been prospectively studied on a large scale.MethodsWe assessed bioequivalence of 42 generic products of 14 immediate-release oral drugs with the highest number of generic products on the Saudi market. We conducted 14 four-sequence, randomized, crossover studies on the reference and three randomly-selected generic products of amlodipine, amoxicillin, atenolol, cephalexin, ciprofloxacin, clarithromycin, diclofenac, ibuprofen, fluconazole, metformin, metronidazole, paracetamol, omeprazole, and ranitidine. Geometric mean ratios of maximum concentration (Cmax) and area-under-the-concentration-time-curve, to last measured concentration (AUCT), extrapolated to infinity (AUCI), or truncated to Cmax time of reference product (AUCReftmax) were calculated using non-compartmental method and their 90% confidence intervals (CI) were compared to the 80.00%–125.00% bioequivalence range. Percentages of individual ratios falling outside the ±25% range were also determined.ResultsMean (SD) age and body-mass-index of 700 healthy volunteers (28–80/study) were 32.2 (6.2) years and 24.4 (3.2) kg/m2, respectively. In 42 generic-reference comparisons, 100% of AUCT and AUCI CIs showed bioequivalence, 9.5% of Cmax CIs barely failed to show bioequivalence, and 66.7% of AUCReftmax CIs failed to show bioequivalence/showed bioinequivalence. Adjusting for 6 comparisons, 2.4% of AUCT and AUCI CIs and 21.4% of Cmax CIs failed to show bioequivalence. In 42 generic-generic comparisons, 2.4% of AUCT, AUCI, and Cmax CIs failed to show bioequivalence, and 66.7% of AUCReftmax CIs failed to show bioequivalence/showed bioinequivalence. Adjusting for 6 comparisons, 2.4% of AUCT and AUCI CIs and 14.3% of Cmax CIs failed to show bioequivalence. Average geometric mean ratio deviation from 100% was ≤3.2 and ≤5.4 percentage points for AUCI and Cmax, respectively, in both generic-reference and generic-generic comparisons. Individual generic/reference and generic/generic ratios, respectively, were within the ±25% range in >75% of individuals in 79% and 71% of the 14 drugs for AUCT and 36% and 29% for Cmax.ConclusionsOn-market generic drug products continue to be reference-bioequivalent and are bioequivalent to each other based on AUCT, AUCI, and Cmax but not AUCReftmax. Average deviation of geometric mean ratios and intra-subject variations are similar between reference-generic and generic-generic comparisons.Trial registration ClinicalTrials.gov identifier: NCT01344070 (registered April 3, 2011).Electronic supplementary materialThe online version of this article (doi:10.1186/s40360-017-0182-1) contains supplementary material, which is available to authorized users.

Activating mutations in the Wnt pathway are a characteristic feature of colorectal cancer (CRC). The R-spondin (RSPO) family is a group of secreted proteins that enhance Wnt signaling and RSPO2 and RSPO3 gene fusions have been reported in CRC. We have previously shown that Wnt pathway blockers exhibit potent combinatorial activity with taxanes to inhibit tumor growth. Here we show that RSPO3 antagonism synergizes with paclitaxel based chemotherapies in patient-derived xenograft models (PDX) with RSPO3 fusions and in tumors with common CRC mutations such as APC, β-catenin, or RNF43. In these latter types of tumors that represent over 90% of CRC, RSPO3 is produced by stromal cells in the tumor microenvironment and the activating mutations appear to sensitize the tumors to Wnt-Rspo synergy. The combination of RSPO3 inhibition and taxane treatment provides an approach to effectively target oncogenic WNT signaling in a significant number of patients with colorectal and other intestinal cancers.

The authors describe a rapid, useful, specific, and very sensitive high-performance liquid chromatographic assay for the determination of fluvastatin (FV) level using atorvastatin as the internal standard (IS). After a simple deproteinization of 1.0 mL of plasma with acetonitrile, the drug and IS were extracted with tert-methyl butyl ether (TMBE). An efficient separation was performed using an 8 mm x 10 cm Nova Pak C(18) 4-microm particle size radial compression cartridge. The mobile phase consisted of an aqueous solution containing 20 mmol/L dibasic sodium dihydrogen phosphate with 1 mmol/L sodium lauryl sulfate adjusted to pH 7 with phosphoric acid and acetonitrile (70:30 v/v) delivered at a flow rate of 1.0 mL/min. The compounds of interest were detected using a fluorescence detector with the excitation wavelength set at 305 nm and the emission at 380 nm. Under these conditions, the retention times for FV and IS were 8.8 and 10.6 minutes, respectively. The concentration of FV in plasma was linear (r > 0.999) for the wide range that was examined (0.5-1,000 ng/mL). The recovery ranged from 88% to 96%. This sensitive, rapid, and simple analytical method gives accurate results over the wide range of concentrations examined. This method is used currently for clinical therapeutic monitoring and pharmacokinetic studies of FV in patients with hypercholesterolemia.

The authors describe a useful and rapid micromethod for the analysis of itraconazole (ITZ) and its active metabolite hydroxyitraconazole (HIT) in human plasma. After a simple deproteinization of 100 microL plasma with acetonitrile, the drug, its metabolite, and an internal standard (IS, ketoconazole) were separated on an 8 mm x 10 cm NovaPak (Waters Associates; Milford, MA) C(18) 4-microm particle-size radial compression cartridge. The compounds of interest were detected using a fluorescence detector with the excitation wavelength set at 260 nm and the emission at 365 nm. The mobile phase consisted of 420 mL water adjusted to a pH of 2.5 with phosphoric acid, 580 mL acetonitrile, and 100 microL triethylamine, which was delivered at a flow rate of 3.0 mL/min. This expedient and rugged method is being used to monitor therapeutic levels in bone marrow transplant recipients who are taking the drug for prophylaxis.

A randomized, single-dose, crossover study was conducted to assess the bioavailability of two domperidone (CAS 57808-66-9) tablet formulations, Domperidone (test) and a commercially available original preparation (reference) under fasting conditions. A 10 mg dose of each formulation was administered to 36 healthy male volunteers with a one-week washout period, 17 blood samples were collected over 48 h, plasma concentrations of domperidone were analyzed by a locally validated LC-MS-MS assay, and the pharmacokinetic parameters were determined by the standard non-compartmental method. Mean +/- SD maximum concentration (C(max)), time to reach maximum concentration (T(max)), areas under the curve (AUC(0 --> t and AUC(0 --> infininty)), and elimination constant (K(el)) were 17.13 +/- 9.62 and 17.67 +/- 7.97 ng/ml, 0.87 +/- 0.58, and 0.89 +/- 0.33 h, 73.12 +/- 43.37 and 71.45 +/- 35.41 ng x h/ml, 90.32 +/- 48.55 and 87.08 +/- 40.29 ng x h/ml, and 0.069 +/- 0.046 and 0.068 +/- 0.048 h(-1) for the test and reference formulation, respectively. The parametric 90% confidence intervals on the mean difference between log-transformed values of the two formulations were within the acceptable bioequivalence range for AUC(0 --> t) (87.84% to 109.60%), AUC(0 --> infinity) (89.05% to 111.67%) and C(max) (83.28% to 107.50%). ANOVA revealed significant subject's effect for AU4C(0 --> t), AUC((0 -->infinity), C(max), and t1/2 with a ratio of the inter-subject to intra-subject coefficient of variation of 2.10, 1.55, 1.10, and 1.02, respectively. The results indicate that the two formulations are equivalent in relation to the extent and rate of absorption and confirm the previously reported marked intra-individual variations in the pharmacokinetics of domperidone.

Objective To evaluate in vitro quality of enteric-coated 50 mg diclofenac sodium tablet formulations on Saudi market. Results A reference and seven generic (G1-7) formulations were commercially available in December 2019/January 2020 and were assessed within 25–75% of manufacture-expiration period. Weight variation (range as% difference from mean, n = 20), active substance content (ASC, mean (SD) as% difference from label, n = 20), hardness (mean (SD), n = 10), and friability (% weight loss, n = 20) were 97–103%, 102.0% (3.4%), 15.4 (1.1) kg, and 0.24%, respectively, for the reference. For G2-7, they were ≤ ±5%, 98.6% (4.0%) to 109.9% (1.8%), 11.9 (0.9) to 18.3 (0.8) kg, and ≤ 0.00 to 0.75%, respectively. G1 ASC, hardness, and friability were 111.3% (1.7%), 20.1 (1.7) kg, and 1.10%, respectively. Disintegration time (n = 6) and dissolution profile (n = 8) were also determined. No formulation disintegrated or released ˃ 0.1% of label ASC in 0.1 N HCl for 2 h. The reference disintegrated in 15:00 min:seconds and released a mean (range) of 100% (99–103%) of label ASC by 45 min in phosphate buffer (pH = 6.8). G1-7 disintegrated in 8:53 to 20:37 min:seconds and released 81% (69–90%) (G1) to 109%. Except for borderline performance of G1, all formulations passed in vitro quality tests according to United States Pharmacopoeia.

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